The overall goal of this program is to define mechanisms that regulate cerebral blood vessels under normal and pathophysiological conditions. The program has successfully integrated emer4ging molecular techniques with more traditional physiological approaches to examine mechanisms that regulate structure and function of the cerebral circulation under normal and pathophysiological conditions. This evolution within the program continues with this renewal as new approaches and investigators continue to be incorporated. The program has several well-defined themes: First, protective mechanisms [nitric oxide, superoxide dismutase (SOD)], and peroxisome proliferator activated receptor (PPAR) in cerebral blood vessels. Second, sources of superoxide within the vessel wall [NAD(P)H oxidase and cyclooxygenase (COX)] and the role of the major cell types-endothelium, smooth muscle, and adventita. Third, pathophysiology and risk factors for cerebral vascular disease and stroke. Modern molecular and mechanistic approaches are used to examine effects of chronic hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia, and inflammation on cerebral vascular structure and function. The Program has several strengths. First, the investigators have a long, productive history of studies of cerebral circulation under physiological and pathophysiological conditions. Second, strong new investigators with key expertise have been integrated into the program. Third, the investigators use diverse, cutting edge approaches altered mice and viral mediated gene transfer, were successfully incorporated during the last funding period and continue to be used heavily. Fourth, the investigators are leaders in several areas of study of the cerebral circulation (endothelial cell biology, nitric oxide, potassium channels, vascular structure) as well as leaders in studies of the impact of cardiovascular risk factors on cerebral vascular biology. The program consists of four projects supported by two core facilities: Administration and Transgenic Animal Core. This integrated, multi- disciplinary approach is intended to facilitate, rapid progress, and more penetrating insight, in understanding mechanisms that regulate cerebral vascular structure and function.